ABSTRACT
BackgroundSARS-CoV-2 has caused a worldwide epidemic of enormous proportions, which resulted in different mortality rates in different countries for unknown reasons. AimWe aimed to evaluate which independent parameters are associated with risk of mortality from COVID-19 in a series that includes all Italian cases, ie, more than 4 million individuals infected with the SARS-CoV-2 coronavirus. MethodsWe analyzed factors associated with mortality using data from the Italian national database of SARS-CoV-2-positive cases, including more than 4 million cases, >415 thousand hospitalized for coronavirus disease-19 (COVID-19) and >127 thousand deceased. For patients for whom age, sex and date of infection detection were available, we determined the impact of these variables on mortality 30 days after the date of diagnosis or hospitalization. ResultsMultivariable Cox analysis showed that each of the analyzed variables independently affected COVID-19 mortality. Specifically, in the overall series, age was the main risk factor for mortality, with HR >100 in the age groups older than 65 years compared with a reference group of 15-44 years. Male sex presented an excess risk of death (HR = 2.1; 95% CI, 2.0-2.1). Patients infected in the first pandemic wave (before 30 June 2020) had a greater risk of death than those infected later (HR = 2.7; 95% CI, 2.7-2.8). ConclusionsIn a series of all confirmed SARS-CoV-2-infected cases in an entire European nation, elderly age was by far the most significant risk factor for COVID-19 mortality, confirming that protecting the elderly should be a priority in pandemic management. Male sex and being infected during the first wave were additional risk factors associated with COVID-19 mortality.
ABSTRACT
Germline variants in genes involved in SARS-CoV-2 cell entry (i.e. ACE2 and TMPRSS2) may influence the susceptibility to infection, as may polymorphisms in genes involved in the innate host response to viruses (e.g. APOBEC3 family). We searched for polymorphisms acting, in lung tissue, as expression quantitative trait loci (eQTLs) for 15 candidate COVID-19 susceptibility genes, selected for their roles in virus cell entry and host antiviral responses. No significant eQTLs were identified for ACE2 and TMPRSS2 genes, whose expression levels did not associate with either sex or age of the 408 patients whose non-diseased lung tissue was analyzed. Instead, we identified seven cis-eQTLs (FDR<0.05) for APOBEC3D and APOBEC3G (rs139296, rs9611092, rs139331, rs8177832, rs17537581, rs61362448, and rs738469). The genetic control of the expression of APOBEC3 genes, which encode enzymes that interfere with virus replication, may explain interindividual differences in risk or severity of viral infections. Future studies should investigate the role of host genetics in COVID-19 patients using a genome-wide approach, to identify other genes whose expression levels are associated with susceptibility to SARS-CoV-2 infection or COVID-19 severity. Author summaryIdentification of expression quantitative trait loci (eQTLs) has become commonplace in functional studies on the role of individual genetic variants in susceptibility to diseases. In COVID-19, it has been proposed that individual variants in SARS-CoV-2 cell entry and innate host response genes may influence the susceptibility to infection. We searched for polymorphisms acting, in non-diseased lung tissue of 408 patients, as eQTLs for 15 candidate COVID-19 susceptibility genes, selected for their roles in virus cell entry and host antiviral responses. Seven cis-eQTLs were detected for APOBEC3D and APOBEC3G genes, which encode enzymes that interfere with virus replication. No significant eQTLs were identified for ACE2 and TMPRSS2 genes. Therefore, the identified eQTLs may represent candidate loci modulating interindividual differences in risk or severity of SARS-CoV-2 virus infection.
